While the identification of smoking-related cancer risk is an important goal, determining the risk of becoming a smoker may be more important from a cancer prevention perspective. In collaboration with Caryn Lerman (Georgetown University) and Neil Caporaso (DCEG, NCI), we have performed a study of 466 smokers and nonsmokers to explore gene-neurobehavioral risk factors for smoking. Here, an interaction for the dopamine transporter and dopamine D2 receptor genes was predictive of smoking and longer times for quitting. Given that nicotine stimulates the secretion of dopamine, which in turn stimulates reward mechanisms, the need for synaptic dopamine and stimulation of dopamine D2 receptors increases the risk for smoking. We also genetic polymorphisms related to depression and smoking and found that persons with subclinical depression were more likely to be smokers if they carried a specific variant of the dopamine D4 receptor. We also studied a genetic polymorphism for tyrosine hydrolase, but no association was found. These studies suggest that the risk of smoking, in addition to common risk factors such as environment, peer pressure and tobacco advertising, may be related to inheritance of genes governing neurotransmitters. A case-control study of lung cancer is continuing in the field with our collaborator Ben Trump (University of Maryland), using the University of Maryland Multi-Organ Contract. To date, 254 subjects have been accrued. All subjects have received phenotyping for host capacity in carcinogen metabolism.